The long-term goal of this project is to understand genetic susceptibility to cardiovascular disease (CVD) and non-insulin dependent diabetes mellitus (NIDDM) in Japanese-American kindreds by characterizing the genetic basis of the risk factors of the metabolic syndrome (insulin resistance syndrome). During the first four years of the project, three specific aims are being addressed, as follow: 1) to determine if variation in the diameter of the major low-density lipoprotein subclass (LDL size) is inherited as a single gene trait in Japanese-American families, and to determine if LDL size is associated with risk factors of the syndrome; 2) to characterize the inheritance of lipoprotein (a) and apolipoprotein (a) isoforms in Japanese Americans; and 3) to establish a repository of white blood cells and plasma aliquots for genetic studies. These aims will be accomplished by the end of the initial 4-year project period, based on data from 400 study participants, including pedigree information, extensive laboratory results, medical history questionnaire data and nutritional data. The project proposed here will enhance these studies by recruiting and sampling approximately 350 additional relatives of local, married-in Japanese-American spouses, with 3 new specific aims: 1) to identify genetic influences on the risk factors that characterize the syndrome (including fasting insulin, proinsulin, C-peptide and glucose; body weight and waist circumference; lipoproteins; blood pressure; fibrinogen, factor VII and plasminogen activator inhibitor-1) using statistical genetic analysis approaches, including univariate complex segregation analysis, factor analysis, and quantitative multivariate genetic analysis; 2) to test for genetic linkage between specific candidate genes involved in lipid metabolism, carbohydrate metabolism, blood pressure, obesity, and hemostasis with genetically influenced risk factors of the metabolic syndrome in Japanese-Americans, using established linkage analysis approaches in sibships and in kindreds; and 3) when the DNA repository has been completed (750 samples by the end of year 4), to apply to the NHLBI Mammalian Genotyping Service to perform a whole genome screen to identify new genes involved in susceptibility to the metabolic syndrome. The investigators state that the studies proposed in this renewal application represent effective ways to characterize genetic susceptibility to the metabolic syndrome and subsequent risk of cardiovascular disease and non-insulin-dependent diabetes among Japanese-American families, and may lead to targeted intervention strategies to prevent these diseases.